A grand challenge in computational chemistry and biology is the accurate quantum mechanical calculation of interaction energies for molecules, especially larger biological molecules such as proteins. Due to a larger number of atoms, standard full quantum mechanical or ab initio calculation of intermolecular interaction energy is beyond computational reach. Currently, most theoretical studies of biological molecules employed classical force fields that are built on pair-wise atomic interaction potentials. Despite the success of classical force field methods in many applications, they still have significant limitations and quantum mechanical calculations of interaction energies are often required, e.g., in studying enzyme reactions.
Recently, a popular approach to applying quantum mechanical calculation to biological molecules is the hybrid quantum mechanical/molecular mechanical (QM/MM) approach in which one combines quantum mechanical methods with molecular force fields for large molecules. In this hybrid QM/MM approach, one employs quantum mechanical or ab initio methods such as Hartree-Fock (HF) or density functional theory (DFT) methods to treat a small subsystem while using molecular force fields to treat the larger part of the system such as solvent molecules. However, the QM/MM approach cannot provide a proper description of the interface between the QM and MM regions because QM and MM approach are inherently incompatible with each other.
Currently, there are two basic approaches to solving this problem: the link atom approach or its variants and the local self-consistent field (LSCF) method, both of which use strictly localized bond orbitals for the bonds between QM and MM atoms. Despite the progress in these approaches in solving the interface problem, some artifacts still exists in applications of QM/MM methods.
Another approach for calculation of large systems is the linear scaling approach in which the large system is divided into small subsystems and the calculation of the large system is performed for each subsystem individually. The linear scaling approach is based on the local property of the interaction because the effect of energy perturbation in one area is generally localized within its vicinity and decays rapidly going away from it. In this approach, the divide-and-conquer (DAC) and similar methods are commonly employed in theoretical calculations. Although these methods scale linearly with the size of the 2 system, applications are currently limited to calculations using semi-empirical methods for proteins. Ab initio calculations of biological molecules using HF or DFT methods are not feasible.
There is thus a need for developing a practical and efficient full quantum mechanical method for calculating interaction energies of molecules such as proteins. This invention answers that need.